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Animal Models for Non-Hereditary and Metastasized Colon Cancers

Posted on December 04, 2014 by Pharma Models Blogging Team in Oncology

Colon cancer is the second leading cause of cancer death in many developed countries and its rates have been increasing among young adults. Numerous established animal models have played a significant role in understanding the molecular events that contribute to colon cancer pathology and in providing a platform for testing new chemopreventive compounds.

Among these animal models, many genetically modified mouse strains have been developed based on two hereditary types of colon cancer: familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). A combination of FAP and HNPCC only accounts for less than 5% of diagnosed colon cancer. In this post, we will focus on animal tools that are associated with non-hereditary types of colon cancer: chemical-induced and implantation models.

Inducible colon cancer models are based on the use of DNA-damaging agents including dimethylhydrazine (DMH), azoxymethane (AOM), 2-amino-1mthyl-6-phenyl-imidazol (4,5-b) pyridine (PHIP), N-methyl-N’-nitro-N-nitrosoguanidine (MNNG), and dimethyl-4-aminobiphenyl (DMBA).

DMH and AOM are potent colon tumor inducers in certain mouse strains whereas PHIP, MNNG, and DMBA have been used more frequently in rats. Colon tumors induced by these carcinogens exhibit similar histopathological characteristics of non-hereditary human colon cancer. Researchers commonly adopt these models because of their additional advantages: simple mode of application, relatively low cost, and dose-dependent susceptibility.

Among these cancer inducers, AMO in combination with dextran sulfate sodium (DSS) treatment in mice can form aberrant crypt foci (early lesions), which provides a useful tool to study early carcinogenic events. The AMO/DSS model significantly shortens the time it takes to develop cancer and – unlike spontaneous cancer generated from genetically altered mice – mainly targets tumor induction to the distal colon. Chronic inflammation induced by DSS also makes the AMO/DSS model a suitable tool to study colon cancer associated with inflammatory bowel disease (IBD).

Metastasis remains the leading cause of colon cancer deaths. In this respect, xenograft models and surgical orthotopic implantation are good options to evaluate the impact of potential therapeutics on the invasiveness and metastasis of the implanted or injected tumor Biomedical researchers commonly apply these transplantation/implantation techniques to immunocompromised mice, such as nude mice that lack T cell function or severely compromised immunodeficient (SCID) mice that lack both B cell and T cell function.

In the grafting models, colon cancer cell lines or tissues from either humans (xenografts) or mice (allografts) are implanted or injected at primary or metastatic tumor sites in immunodeficient mice. Certain human cancer cell lines have the ability to be metastasized after intrarectal implantation. For example, the human colon cancer cell line HT-29 produces locally aggressive rectal tumors, which subsequently metastasize to the lymph nodes.

Orthotopic implantation allows for injection of human colon cancer cells into mouse intestinal serosa and produces a model more similar to human colon cancer than subcutaneous xenografts. Through surgical orthotopic procedures, implanting human colon cancer-derived liver metastasis cells leads to their metastasizing to the liver, peritoneum, lymph nodes, and spleen. In addition to being more clinically relevant, orthotopic colon tumor models have an advantage in that the tumor growth, distribution, and metastatic site can be monitored by using tumor cells carrying a luciferase reporter gene.

To overcome the drawbacks of the conventional orthotopic procedure – it is technically complex and can cause procedure-related inflammation and death – an improved orthotopic mouse model has been established by adapting the murine colonoscopy system. In this model, tumor incidence and location within the colon can be precisely controlled; both human and murine colon tumors can be implanted in mice from any genetic background; and the procedure is more straightforward, relatively non-invasive, and has good reproducibility.